Compounds and methods for treating urinary incontinence

ABSTRACT

The present invention relates to the use of α 1L -agonists for treating urinary incontinence.

[0001] The present invention relates to the use of α_(1L)-agonists fortreating urinary incontinence, particularly stress incontinence.

[0002] The cause of stress incontinence in women is usually weakness ofthe pelvic floor, e.g. after numerous difficult births. However, it mayalso be due to nerve disorders of the pelvic floor, a congenitally shorturethra or, occasionally, damage to the sphincter caused by surgery. Thereduction in the oestrogen levels post-menopause further encouragesstress incontinence.

[0003] The term stress incontinence refers to a sudden loss of urine,which is caused by incompetence of the bladder outlet during unobtrusivemovement of the bladder as a result of interabdominal increases inpressure due to coughing, pressing, sneezing, heavy lifting, etc.

[0004] Surprisingly, it has been found that the α_(1L)-subtype of theadrenergic receptor has a significant effect on the continence mechanismof urether tonicisation.

[0005] The invention relates to the use of α_(1L)-adrenoceptor agonistsfor treating urinary incontinence, particularly stress incontinence, andfor preparing drugs for treating urinary incontinence, particularlystress incontinence. It is particularly interesting to use aminoimidazolines of general formula

[0006] and the pharmacologically acceptable acid addition salts thereof.

[0007] In general formula I

[0008] Y denotes an optionally substituted phenyl or napthyl group or

[0009] Y denotes a 5- or 6-membered, optionally fully unsaturated,optionally substituted heterocyclic ring which contains oxygen, sulphuror nitrogen as heteroatoms, and

[0010] X denotes —NH—, —CH₂—, —OCH₂—, —O—CHCH₃—, —CH═N—NH—, —N═N— or—NZ—, wherein Z=—CH₂—CH═CH₂ or cyclopropylmethyl.

[0011] Preferred compounds are those wherein X is —NH— and/or Y is anoptionally substituted thienyl, furyl, pyrrole, tetrahydropyrrole,pyridyl, pyrazinyl, pyranyl, 1,3-thiazolyl, imidazolyl, imidazolinyl,1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, isothiazolyl, pyrimidinyl,thiazolyl, thiadiazinyl or piperidinyl, bound to the group X via a Catom. It is preferred to use tiamenidine.

[0012] Preferred compounds for this purpose are imidazolines of generalformula

[0013] or imidazolines of general formula

[0014] wherein

[0015] R¹, R², R R⁴ and RS denote, independently of one another:hydrogen, C₁₋₆-alkyl, preferably C₁₋₄-alkyl, most preferably methyl,C₃₋₆-cycloalkyl, preferably cyclopropyl, C₁₋₆-alkoxy, preferablyC₁₋₄-alkoxy, most preferably methoxy, halogen, preferably chlorine orbromine, —CF₃, —OCF₃ or —NR⁶R⁷ wherein

[0016] R⁶ denotes hydrogen, C_(3—6)-cycloalkyl, C₁₋₆-alkyl, preferablyC₁₋₄-alkyl, most preferably methyl, or C₂₋₄-acyl, most preferablyacetyl,

[0017] R⁷-denotes hydrogen, C₃₋₆-cycloalkyl, preferably cyclopropyl,C₁₋₆-alkyl, preferably C₁₋₄-alkyl, most preferably methyl, or C₂₋₄-acyl,most preferably acetyl; or

[0018] R⁶ and R⁷ together with the nitrogen atom form a 5- or 6-memberedsaturated or unsaturated ring which may contain up to two furtherheteroatoms selected from oxygen, sulphur or nitrogen, whilst eachadditional nitrogen atom may be substituted by C₁₋₄-alkyl, preferablymethyl;

[0019] or R⁶ and R⁷ together with the nitrogen atom form phthalimido; or

[0020] R¹ and R² together form a fused pyrazole of formula

[0021] wherein R⁸ is C₁₋₃-alkyl, preferably methyl;

[0022] or a fused thiadiazole of formula

[0023] wherein R³, R⁴ and R⁵ are as hereinbefore defined, and preferablydenote hydrogen,

[0024] and the pharmacologically acceptable acid addition salts thereof.

[0025] Formulae I and I′ and Ib and II are equivalent tautomericstructures. The preparation of one structure (e.g. Ib) includes theother structure (e.g. II) in each case.

[0026] Also preferred are imidazolines of general formula Ib

[0027] wherein

[0028] R¹ denotes hydrogen, ethyl, methyl, fluorine, chlorine, bromineor CF₃,

[0029] R² denotes methyl, fluorine, chlorine, bromine or —NR⁶R⁷, wherein

[0030] R⁶ denotes hydrogen, C₁₋₄-alkyl, preferably methyl, C₂₋₄-acyl,preferably acetyl and

[0031] R⁷ denotes hydrogen, C₁₋₄-alkyl, preferably methyl, C₂₋₄-acyl,preferably acetyl or

[0032] R⁶ and R⁷ together with the nitrogen atom form phthalimido;

[0033] R³ denotes hydrogen, fluorine, chlorine, bromine, C₁₋₄-alkyl,preferably methyl, NH₂ or cyclopropyl;

[0034] R⁴ denotes hydrogen, C₁₋₄-alkyl, preferably methyl, fluorine,chlorine, bromine or CF₃;

[0035] R⁵ denotes hydrogen, C₁₋₄-alkyl, preferably ethyl or methyl,fluorine, chlorine, bromine or CF₃; or

[0036] R¹ and R² together form a fused pyrazole of formula

[0037] wherein R⁸ is methyl,

[0038] or a fused thiadiazole of the formula

[0039] wherein R³, R⁴ and Rs are as hereinbefore defined, and preferablyrepresent hydrogen; particularly those wherein

[0040] R¹ is hydrogen or methyl;

[0041] R² is methyl, chlorine, CF₃, NH₂ or N(CH₃)₂;

[0042] R³ is hydrogen, methyl, chlorine or bromine;

[0043] R⁴ is hydrogen;

[0044] R⁵ is hydrogen, methyl, methoxy, chlorine or bromine.

[0045] Particular mention should be made of the use of

[0046] 2-(3-dimethylamino-2-methylphenylimino)imidazolidine,

[0047] 2-(6-bromo-3-dimethylamino-2-methylphenylimino)imidazolidine,

[0048] 2-(5-amino-2-chloro-4-methylphenylimino)-imidazolidine,

[0049] 2-(3-amino-2-methylphenylimino)-imidazolidine or

[0050] 2-(2-chloro-5-trifluoromethylphenylimino)-imidazolidine.

[0051] Examples of heterocyclic groups —NR⁶R⁷ are as follows:

[0052] pyrrole, Δ²-pyrroline, Δ³-pyrroline, tetrahydropyrrole,pyrrolidine, pyrrolidinone, imidazole, imidazoline, 1,3-thiazole,piperidine, piperazine, 4-C₁₋₄-alkylpiperazine, C₁₋₄-alkylpiperazine,2,5-diketopiperazine, preferably N-methylpiperazine, morpholine,thiomorpholine, phthalimido or succinimido.

[0053] Examples of alkyl within the above definitions, including thosewhich are components of other groups, are branched or unbranchedC₁₋₆-alkyl groups, e.g. methyl, ethyl, n-propyl, isopropyl, isobutyl,n-butyl, isobutyl, sec.-butyl and tert.-butyl, n-pentyl, isopentyl,neopentyl, hexyl and isohexyl.

[0054] Cycloalkyl generally represents a saturated cyclic hydrocarbongroup having 3 to 6 carbon atoms which may optionally be substitutedwith a halogen atom or several halogen atoms, a hydroxy group, an alkylgroup, preferably methyl, which may be the same as or different from oneanother. Examples include cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl.

[0055] Some of the imidazolines defined in general formula Ib are new.The invention therefore also relates to new substituted2-phenylimino-imidazolidines, their use in pharmaceutical compositionsand to processes for preparing them.

[0056] 2-(Phenylimino)-imidazolidines, the preparation thereof and theiruse as pharmaceutical compositions are known, for example from GermanPatent Application Nos. DE-OS-19 29 950 and DE-OS-23 16 377, in whichthe hypotensive properties of the compounds described are particularlyemphasised.

[0057] New substituted 2-(phenylimino)-imidazolidines of general formulaII

[0058] have surprising pharmacological properties and are particularlysuitable for treating urinary incontinence.

[0059] The invention thus relates to compounds of general formula II

[0060] wherein

[0061] R¹ denotes hydrogen, C₁₋₆-alkyl, preferably C₁₋₄-alkyl, mostpreferably methyl, C₃₋₆-cycloalkyl, preferably cyclopropyl, C₁₋₆-alkoxy,preferably C₁₋₄-alkoxy, most preferably methoxy, halogen, preferablychlorine or bromine, —CF₃ or —OCF₃;

[0062] R² denotes —NR⁶R⁷ wherein

[0063] R⁶ denotes hydrogen, C₃₋₆-cycloalkyl, C₁₋₆-alkyl, preferablyC₁₋₄-alkyl, most preferably methyl, C₂₋₄-acyl, most preferably acetyl;

[0064] R⁷ denotes hydrogen, cyclopropyl, C₃₋₆-cycloalkyl, C₁₋₆-alkyl,preferably C₁₋₄-alkyl, most preferably methyl, C₂₋₄-acyl, mostpreferably acetyl;

[0065]  or

[0066] R⁶ and R⁷ together with the nitrogen atom form a 5- or 6-memberedsaturated or unsaturated ring which may contain up to two additionalheteroatoms selected from the group of oxygen, sulphur or nitrogen,whilst each additional nitrogen atom may be substituted by C₁₋₄-alkyl,preferably methyl; or R⁶, and R⁷ together with the nitrogen atom fromphthalimido;

[0067] R³ denotes hydrogen, halogen, C₁₋₆-alkyl, preferably C₁₋₄-alkyl,most preferably methyl, C₁₋₆-alkoxy, preferably C₁₋₄-alkoxy, mostpreferably hydrogen, methoxy, —CF₃ or —OCF₃;

[0068] R⁴ denotes hydrogen, C₁₋₆-alkyl, preferably C₁₋₄-alkyl, mostpreferably methyl, hydrogen or halogen;

[0069] R⁵ denotes hydrogen, C₁₋₆-alkyl, preferably C₁₋₄-alkyl, mostpreferably methyl, C₁₋₆-alkoxy, preferably C₁₋₄-alkoxy, most preferablymethoxy, halogen, —CF₃ or —OCF₃,

[0070] and the pharmacologically acceptable acid addition salts thereof,with the exception of 2-(3-diethylamino-2-methyl)-imidazolidine.

[0071] Preferred compounds of general formula II are those wherein

[0072] R¹ denotes hydrogen, C₁₋₄-alkyl, cyclopropyl, C₁₋₄-alkoxy,halogen, CF₃ or —OCF₃;

[0073] R² denotes —NR₆R₇ wherein

[0074] R⁶ is hydrogen, C₃₋₆-cycloalkyl, C₁₋₄-alkyl or acetyl,

[0075] R⁷ is hydrogen, cyclopropyl C₁₋₄-alkyl or acetyl, or

[0076] R⁶ and R⁷ together with the nitrogen atom form phthalimido;

[0077] R³ is hydrogen, halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, CF₃ or —OCF₃;

[0078] R⁴ is hydrogen, C₁₋₄-alkyl, methyl, halogen;

[0079] R⁵ is hydrogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, halogen, CF₃ or —OCF₃;particularly those wherein

[0080] R¹ is hydrogen, C₁₋₃-alkyl, n-butyl, isobutyl, sec.-butyl,preferably methyl, cyclopropyl, C₁₋₃-alkoxy, preferably methoxy,halogen, preferably chlorine or bromine, CF₃;

[0081] R² denotes —NR₆R₇ wherein

[0082] R⁶ is hydrogen, cyclopropyl, C₁₋₄-alkyl, preferably methyl,

[0083] R⁷ denotes hydrogen, C₁₋₄-alkyl, preferably methyl, or R⁶ and R⁷together with the nitrogen atom form phthalimido;

[0084] R³ denotes hydrogen, C₁₋₃-alkyl, n-butyl, isobutyl, sec.-butyl,preferably methyl, cyclopropyl, C₁₋₃-alkoxy, preferably methoxy,halogen, preferably chlorine or bromine, CF₃;

[0085] R⁴ denotes hydrogen, C₁₋₃-alkyl, n-butyl, isobutyl, sec.-butyl,preferably methyl, cyclopropyl, C₁₋₃-alkoxy, preferably methoxy,halogen, preferably chlorine or bromine;

[0086] R⁵ denotes hydrogen, C₁₋₃-alkyl, n-butyl, isobutyl, sec.-butyl,preferably methyl, cyclopropyl, C₁₋₃-alkoxy, preferably methoxy,halogen, preferably chlorine or bromine, CF₃; particularly those wherein

[0087] R¹ is hydrogen or methyl,

[0088] R² is —NR⁶R⁷ wherein

[0089] R⁶ and R⁷ independently of each other denote hydrogen, methyl ormethoxy or

[0090] R⁶ and R⁷ together with the nitrogen atom form phthalimido;

[0091] R³ denotes hydrogen, methyl, fluorine, chlorine or bromine;

[0092] R⁴ denotes hydrogen,

[0093] R⁵ denotes hydrogen, methyl, chlorine or bromine;

[0094] and the pharmacologically acceptable acid salts thereof,especially the hydrobromides or hydrochlorides thereof.

[0095] Particular mention should be made of the following compounds, forexample:

[0096] 2-(3-dimethylamino-2-methylphenylimino)imidazolidine,

[0097] 2-(6-bromo-3-dimethylamino-2-methylphenylimino)imidazolidine,

[0098] 2-(5-amino-2-chloro-4-methylphenylimino)-imidazolidine and

[0099] 2-(3-amino-2-methylphenylimino)-imidazolidine.

[0100] The compounds of general formula I and II may be preparedaccording to analogous processes known per se from the prior art. Aselection of the preferred processes are shown in the followingsynthetic schemes with reference to concrete Examples.

[0101] The preferred processes for preparing the compounds according tothe invention will be explained with reference to individual Examples.

[0102] The methylation of the starting material,2-methyl-3-nitro-aniline, may also be carried out analogously to theLeuckart-Wallach reaction using HCOOH/CH₂O or using dimethylcarbonateinstead of dimethylsulphate.

[0103] Compound 2 can be prepared by bromination of compound 1 underconventional reaction conditions

EXAMPLE 2

[0104] The following synthetic scheme illustrates the preparation ofcompounds 2, 3 and 4

[0105] Other alternative methods of synthesis are, illustrated below.

[0106] Compound 5 and compounds of similar structure can be preparedanalogously to a method described by N. R. Ayyangar (Synthesis 1987,64).

EXAMPLE 1

[0107] 2-(3-Dimethylamino-2-methylphenylimino) imidazolidine

[0108] 1st Step:

[0109] 83.6 g of 2-methyl-3-nitroaniline, 190 g of K₂CO₃ and 260 ml ofwater are together heated to 100° C. 27 ml of dimethylsulphate are addeddropwise over 1 hour, then the mixture is heated for a further hour.After cooling to ambient temperature, the top layer is removed and theaqueous phase remaining is extracted four times with ether.

[0110] The combined ether extracts are combined with the upper layer,dried with MgSO₄ and evaporated down in vacuo. 73 g ofN,N-dimethyl-2-methyl-3-nitroaniline are obtained.

[0111] 2nd Step:

[0112] 73 g of N,N-dimethyl-2-methyl-3-nitroaniline are dissolved in 800ml of methanol and hydrogenated at 20° C. under 5 bar of hydrogen usingRaney nickel as catalyst. 57 g of 3-dimethylamino-2-methylaniline areobtained.

[0113] 3rd Step:

[0114] 57 g of 3-dimethylamino-2-methyl-aniline, 1.15 litres of acetone,36.6 g of KSCN and 43.8 ml of benzoylchloride are refluxed together for3 hours. After cooling to ambient temperature the reaction mixture ispoured onto 2.4 kg of crushed ice. The precipitate obtained is heated to60° C. for 2 hours together with 85 g of KOH, 85 ml of water and 255 mlof ethanol. After the addition of 850 ml of water the ethanol isdistilled off under reduced pressure. After the resulting precipitatehas been worked up, 72 g of N-(3-dimethylamino-2-methylphenyl)-thioureaare obtained.

[0115] 4th Step:

[0116] 72 g of the thiourea from Step 3 are taken up in 345 ml ofmethanol and after the addition of 22.6 ml of methyliodide the mixtureis refluxed for 2 hours. The resulting solution is evaporated down underreduced pressure; 120 g ofN-(3-dimethylamino-2-methylphenyl)-S-methyl-isothiourea hydroiodide areobtained.

[0117] 5th Step:

[0118] 120 g of the thiourea from Step 4 in 350 ml of methanol arecombined with 34.4 ml of 1,2-diaminoethane and refluxed for 17 hours.The reaction mixture is then evaporated down in vacuo and the residue istaken up in water. The pH is adjusted to 7 using dilute hydrochloricacid. The aqueous phase is extracted 3 times with ethyl acetate. Thenthe aqueous phase is made alkaline with 5N NaOH and extracted a further3 times with ethyl acetate, these extracts are combined, dried withMgSO₄ and evaporated down in vacuo. An oil is obtained which ischromatographed over silica gel (eluant toluene, dioxane, ethanol,ammonia 10:8:3:1=“Super-T”)

[0119] 17.9 g of 2-(3-dimethylamino-2-methylphenyl-imino)-imidazolidineare obtained.

[0120] Melting point 116-118° C.

EXAMPLE 2

[0121] 2-(6-Bromo-3-dimethylamino-2-methylphenylimino) imidazolidine

[0122] 6.55 g of 2-(3-Dimethylamino-2-methylphenyl-imino)-imidazolidineare dissolved in 75 ml of chloroform and 1.53 ml of bromine are added,with stirring, at 0° C. After 2 hours at 0° C. the solution isevaporated down under reduced pressure and the residue thus obtained ismixed with dilute hydrochloric acid. The aqueous solution is extractedtwice with ether, then the aqueous phase is made alkaline with diluteNaOH and extracted three more times with ether. The combined etherextracts are evaporated down under reduced pressure and the residueremaining is worked up by chromatography (silica gel, eluant “Super-T”(Example 1)).

[0123] 3.4 g of2-(6-bromo-3-dimethylamino-2-methyl-phenylimino)-imidazolidine areobtained, Mp. 157-158° C., as a white powder.

[0124] The following compounds were prepared analogously to theprocesses described:

[0125] 2-(4-bromo-3-dimethylamino-2-methylphenylimino)-imidazolidine

[0126] 2-(4,6-dibromo-3-dimethylamino-2-methylphenylimino)-imidazolidine

[0127] 2-(6-chloro-3-dimethylamino-2-methylphenylimino)-imidazolidine

[0128] 2-(3-acetylamino-6-chlorophenylimino)-imidazolidine, Mp. 236-238°C.

[0129] 2-(2-methyl-3-phthalimidophenylimino)-imidazolidine, Mp. 189-190°C.

[0130] 2-(6-chloro-3-phthalimidophenylimino)-imidazolidine, Mp. 239-241°C.

[0131] 2-(5-amino-2-chloro-4-methylphenylimino)-imidazolidine, Mp.155-157° C.

[0132] 2-(3-amino-4-fluorophenylimino)-imidazolidine, (2HCl), Mp. 222°C.

[0133] 2-(3-amino-4-methylphenylimino)-imidazolidine, (HCl),

[0134] 2-(3-amino-6-methylphenylimino)-imidazolidine, (HCl), Mp.194-196° C.

[0135] 2-(3-amino-6-chlorophenylimino)-imidazolidine, (HCl), Mp.197-198° C.

[0136] 2-(3-amino-4,6-dibromo-2-methylphenylimino)-imidazolidine, Mp.154-155° C.

[0137] 2-(3-amino-2-methylphenylimino)-imidazolidine, (HCl), Mp.204-206° C.

[0138] The following compounds are specifically mentioned by name:

[0139] 2-(2,6-diethylphenyl-imino)-imidazolidine

[0140] 2-(2-chloro-6-methylphenylimino)-imidazolidine

[0141] 2-(2,6-dichloro-phenylimino)-imidazolidine

[0142] 2-(2-chloro-4-methylphenylimino)-imidazolidine

[0143] 2-(2,4-dichlorophenylimino)-imidazolidine

[0144] 2-(2-chloro-5-trifluoromethylphenylimino)-imidazolidine

[0145] 2-(5-fluoro-2-methylphenylimino)-imidazolidine

[0146] 2-(3-bromo-2-methylphenylimino)-imidazolidine

[0147] 2-(2-chloro-3-methylphenylimino)-imidazolidine

[0148] 2-(2-fluoro-6-trifluoromethylphenylimino)-imidazolidine

[0149] 2-(2-chloro-4-cyclopropylphenylimino)-imidazolidine

[0150] 2-(4-amino-3,5-dibromophenylimino)-imidazolidine

[0151] 2-(3-fluoro-4-methylphenylimino)-imidazolidine

[0152] 2-(6-bromo-2-fluorophenylimino)-imidazolidine

[0153] 4-(2-imidazolin-2-ylamino)-2-methylindazole

[0154] 5-chloro-4-(imidazolin-2-yl-amino)-benzothiadiazole (Tizanidine)

[0155] 2-[(2-chloro-4-methyl-3-thienyl)amino]-2-imidazoline(Tiamenidine)

[0156] 2-(2,5-dichlorophenylimino)-imidazolidine

[0157] The compounds of general formulae I and II according to theinvention may be converted into their physiologically acceptable acidaddition salts in the usual way. Examples of acids suitable for saltformation include, for example, inorganic acids such as hydrochloricacid, hydrobromic acid, hydiodic acid, hydrofluoric acid, sulphuricacid, phosphoric acid, nitric acid or organic acids such as acetic acid,propionic acid, butyric acid, caproic acid, capric acid, valeric acid,oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid,lactic acid, tartaric acid, citric acid, malic acid, benzoic acid,p-hydroxybenzoic acid, p-aminobenzoic acid, phthalic acid, cinnamicacid, salicylic acid, ascorbic acid, methanesulphonic acid andethanephosphonic acid.

[0158] The corresponding hydrobromides and hydrochlorides are preferredas the acid addition salts.

[0159] Pharmaceutical compositions comprising the compounds describedmay be used in the form of capsules, suppositories, solutions, syrups,emulsions or dispersible powders. Corresponding tablets may be obtained,for example, by mixing the active substance or substances with knownexcipients such as inert diluents, e.g. calcium carbonate, calciumphosphate or lactose, disintegrants such as corn starch or alginic acid,binders such as starch or gelatine, lubricants such as magnesiumstearate or talc, and/or agents for obtaining delayed release, such ascarboxypolymethylene, carboxymethylcellulose, cellulose acetatephthalate, or polyvinyl acetate. The tablets may also consist of severallayers.

[0160] Coated tablets may be produced accordingly, by coating cores madeanalogously to the tablets with agents conventionally used for tabletcoating, e.g. collidone or shellac, gum arabic, talc, titanium dioxideor sugar. In order to achieve delayed release or preventincompatibilities, the core may also consist of several layers.Similarly, the tablet coating may consist of several layers in order toachieve delayed release, and the excipients mentioned for the tabletsmay be used.

[0161] Syrups of the active substances or combinations of activesubstances according to the invention may additionally contain asweetener such as saccharin, cyclamate, glycerol or sugar and a flavourenhancer, e.g. a flavouring such as vanillin or orange extract. They mayalso contain suspension adjuvants or thickeners such as sodiumcarboxymethylcellulose, wetting agents, e.g. condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

[0162] Injectable solutions are prepared in the usual way, e.g. byadding preservatives such as p-hydroxybenzoates or stabilisers such asalkali metal salts of ethylenediamine tetraacetic acid and are thentransferred into injection vials or ampoules.

[0163] The capsules containing the active substance or combination ofactive substances may be prepared, for example, by mixing the activeingredients with inert carriers such as lactose or sorbitol andpackaging the mixture in gelatine capsules.

[0164] Suitable suppositories may be produced, for example, by mixingwith carriers provided for this purpose such as neutral fats ofpolyethyleneglycol or derivatives thereof.

[0165] For transdermal application the active substances according tothe invention may be incorporated in suitable carriers (plasters), e.g.made of polyacrylates. Suitable adjuvants may be used in order toincrease the release rate.

[0166] For oral administration a dosage of 1 to 50 mg is proposed as atherapeutically single dose.

EXAMPLE A Tablets

[0167] 2-(3-Dimethylamino-2-methylphenylimino)- 10 mg inxidazolidine.HBrLactose 65 mg Corn starch 125 mg  sec. Calcium phosphate 40 mg Solublestarch  3 mg Magnesium stearate  4 mg Colloidal silica  4 mg Total 251mg 

[0168] Preparation:

[0169] The active substance is mixed with some of the excipients,kneaded intensively with an aqueous solution of the soluble starch andgranulated with a sieve in the usual way. The granules are combined withthe remaining excipients and compressed into tablet cores weighing 250mg which are then coated in the usual way using sugar, talc and gumarabic.

EXAMPLE B Ampoules

[0170] 2-(3-Dimethylamino-2-methylphenylimino)-  1.0 mgimidazolidine.HBr Sodium chloride 18.0 mg Sufficient distilled water tomake up to  2.0 ml

[0171] Preparation:

[0172] The active substance and sodium chloride are dissolved in waterand transferred into glass ampoules under nitrogen.

EXAMPLE C Drops

[0173] 2-(3-Dimethylamino-2-methylphenylimino)- 0.02 g imidazolidine.HBrMethyl p-hydroxybenzoate 0.07 g Propyl p-hydroxybenzoate 0.03 gSufficient demineralised water to make up to  100 ml

EXAMPLE D Injectable Solution

[0174] 2-(3-Dimethylamino-2-methylphenylimino)-  1.5 partsimidazolidine.HBr Sodium salt of ethylenediamine tetraacetic acid  0.2parts Sufficient distilled water to make up to 100.0 parts

[0175] Preparation:

[0176] The active substance and the sodium salt of ethylenediaminetetraacetic acid are dissolved in sufficient water and topped up to thedesired volume with water. The solution is filtered to remove anysuspended particles and transferred into 2 ml ampoules under asepticconditions. Finally, the ampoules are sterilised and sealed. Eachampoule contains 20 mg of active substance.

[0177] One advantage of the compounds described is that they actprimarily on the urethra and have little or no effect on thecardiovascular system.

[0178] The selective pharmacological activity of the compounds accordingto the invention is demonstrated by the compound of Example2-2-(6-bromo-3-dimethylamino-2-methylphenylimino)-imidazolidine—and acomparison compound, phenylephrine, by measuring the intraluminalpressure of the urethra and blood pressure in the rabbit.

[0179] Female Japanese white rabbits (weighing 3.0 to 3.5 kg) areanaesthetised with urethane (1 g/kg i.p.). A polyethylene cannula isinserted in the urinary bladder by means of a small incision. Thechanges in the intraluminal pressure are recorded by means of balloon inthe urethra which contains about 1.5 ml of water at 37° C. Theintraurethral pressure is recorded on a polygraph by means of apressure-voltage transducer.

[0180] The neck is opened up and the carotid artery is cannulated inorder to measure the blood pressure and at the same time the trachea isintubated in order to maintain breathing. The changes in blood pressureare recorded on a polygraph by means of a pressure-voltage transducer.Heart rate is measured using a tachometer.

[0181] Phenylephrine and the compound of Example 2 are introduced intothe Vena femoralis i.v. through a polyethylene cannula. Dosages of 30μg/kg of phenylephrine are compared with 10 μg/kg of the compound ofExample 2.

[0182] Compared with phenylephrine the compound of Example 2 accordingto the invention exhibits a potency which is higher by a factor of 2.73with regard to the contraction of the urethra and with a duration ofeffect which is longer by a factor of 4.3. By comparison, the increasein blood pressure with the compound according to the invention is only1.39 times that of the comparison compound phenylephrine. It is notablethat the increase in blood pressure is prolonged only to aninsignificant degree (by a factor of 1.17) compared with phenylephrine.These experiments show that the compounds according to the inventionhave a selective effect on the urethra. Being selectiveα_(1L)-adrenoreceptor agonists, the compounds according to the inventionare suitable for treating problems of urinary incontinence, particularlyfor treating stress incontinence.

[0183] The test results are shown in Table 1. TABLE 1 ContractionIncrease of the Duration in blood Duration urethra of effect pressure ofeffect Phenylephrine 100 100 100 100 Example 2 273 430 139 117

1. Use of α_(1L)-agonists for the preparation of pharmaceuticalcompositions for treating urinary incontinence, particularly stressincontinence.
 2. Use according to claim 1, in which the α_(1L)-agonistshave the general formula I

wherein Y denotes an optionally substituted phenyl or napthyl group or Ydenotes a 5- or 6-membered, optionally fully unsaturated, optionallysubstituted heterocyclic ring which contains oxygen, sulphur or nitrogenas heteroatoms, and X denotes —NH—, —CH₂—, —OCH₂—, —O—CHCH₃—, —CH═N—NH—,—N═N— or —NZ—, wherein Z=—CH₂—CH═CH₂ or cyclopropylmethyl, and thepharmacologically acceptable acid addition salts thereof.
 3. Useaccording to claim 2, wherein X in the compound of formula I denotes—NH—.
 4. Use according to claim 2 or 3, wherein in the compound offormula I Y is an optionally substituted thienyl, furyl, pyrrole,tetrahydropyrrolyl, pyridyl, pyrazinyl, pyranyl, 1,3-thiazolyl,imidazolyl, imidazolinyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl,isothiazolyl, pyrimidinyl, thiazolyl, thiadiazinyl or piperidinyl, whichis bound to the group X via a carbon atom.
 5. Use according to one ofclaims 2 to 4, wherein the compound of formula I is tiamenidine.
 6. Useof phenylaminoimidazolines of general formula Ib

wherein R¹, R², R³, R⁴ and R⁵ denote, independently of one another:hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₁₋₆-alkoxy, halogen, —CF₃, —OCF₃or —NR⁶R⁷ wherein R⁶ denotes hydrogen, C₃₋₆-cycloalkyl, C₁₋₆-alkyl orC₂₋₄-acyl, R⁷ denotes hydrogen, C₃₋₆-cycloalkyl, C₁₋₆-alkyl orC₂₋₄-acyl; or R⁶ and R⁷ together with the nitrogen atom form a 5- or6-membered saturated or unsaturated ring which may contain up to twoadditional heteroatoms from the group comprising oxygen, sulphur ornitrogen, whilst each additional nitrogen atom may be substituted byC₁₋₄-alkyl; or R⁶ and R⁷ together with the nitrogen atom formphthalimido; or R¹ and R² together form a fused pyrazole of the formula

 wherein R⁸ is C₁₋₃-alkyl,  or a fused thiadiazole of the formula

 wherein R³, R⁴ and Rs are as hereinbefore defined, and thepharmacologically acceptable acid addition salts thereof, for preparingpharmaceutical composition for treating urinary incontinence,particularly stress incontinence.
 7. Use of phenyliminoimidazolines ofgeneral formula Ib according to claim 6, wherein R¹, R², R³, R⁴ and R⁵independently of one another denote: hydrogen, C₁₋₄-alkyl, preferablymethyl, cyclopropyl, C₁₋₄-alkoxy, preferably methoxy, halogen, CF₃,—OCF₃ or NR⁶R⁷ wherein R⁶ is hydrogen, C₃₋₆-cycloalkyl, C₁₋₄-alkyl,preferably methyl, or acetyl, R⁷ denotes hydrogen, cyclopropyl,C₁₋₄-alkyl, preferably methyl, or acetyl; or R⁶ and R⁷ together with thenitrogen atom form phthalimido; or R¹ and R² together form a fusedpyrazole of the formula

 wherein R⁸ is methyl,  or a fused thiadiazole of the formula

 wherein R³, R⁴ and R⁵ are as hereinbefore defined, and preferablyrepresent hydrogen.
 8. Use of phenylaminoimidazolines of general formulaIb according to claim 6, wherein R¹, R², R³, R⁴, R⁵ independently of oneanother denote: hydrogen, ethyl, methyl, cyclopropyl, fluorine,chlorine, bromine, —CF₃ or —NR⁶R⁷ wherein R⁶ denotes hydrogen, methyl oracetyl, R⁷ denotes hydrogen, methyl or acetyl; or R⁶ and R⁷ togetherwith the nitrogen atom form phthalimido; or R¹ and R² together form afused pyrazole of the formula

 wherein R⁸ is methyl,  or a fused thiadiazole of the formula

 wherein R³, R⁴ and R⁵ are as hereinbefore defined, and preferablyrepresent hydrogen.
 9. Use of phenylaminoimidazolines of general formulaIb according to claim 6, wherein R¹ denotes hydrogen, ethyl, methyl,fluorine, chlorine, bromine or —CF₃, R² denotes methyl, fluorine,chlorine, bromine or —NR⁶R⁷, wherein R⁶ denotes hydrogen, C₁₋₄-alkyl,preferably methyl, C₂₋₄-acyl, preferably acetyl and R⁷ denotes hydrogen,C₁₋₄-alkyl, preferably methyl, C₂₋₄-acyl, preferably acetyl or R⁶ and R⁷together with the nitrogen atom form phthalimido; R³ denotes hydrogen,fluorine, chlorine, bromine, C₁₋₄-alkyl, preferably methyl, —NH₂ orcyclopropyl; R⁴ denotes hydrogen, C₁₋₄-alkyl, preferably methyl,fluorine, chlorine, bromine or —CF₃; R⁵ denotes hydrogen, C₁₋₄-alkyl,preferably ethyl or methyl, fluorine, chlorine, bromine or —CF₃; or R¹and R² together form a fused pyrazole of formula

 wherein R⁸ is methyl,  or a fused thiadiazole of the formula

 wherein R³, R⁴ and Rs are as hereinbefore defined, and preferablyrepresent hydrogen.
 10. Use of phenylaminoimidazolines of formula Ibaccording to claim 6, wherein R¹ is hydrogen or methyl; R² is methyl,chlorine, —CF₃, —NH₂ or —N(CH₃)₂; R³ is hydrogen, methyl, chlorine orbromine; R⁴ is hydrogen; R⁵ is hydrogen, methyl, methoxy, chlorine orbromine.
 11. Use of phenylaminoimidazolines of formula Ib according toclaim 6, wherein the compound is2-(3-dimethylamino-2-methylphenylimino)imidazolidine,2-(6-bromo-3-dimethylamino-2-methylphenylimino)imidazolidine,2-(5-amino-2-chloro-4-methylphenylimino)-imidazolidine,2-(3-amino-2-methylphenylimino)-imidazolidine or2-(2-chloro-5-trifluoromethylphenylimino)-imidazolidine.
 12. Newphenyliminoimidazolidines of general formula II

wherein R¹ denotes hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₁₋₆-alkoxy,halogen, —CF₃ or —OCF₃; R² denotes —NR⁶R⁷ wherein R⁶ is hydrogen,C₃₋₆-cycloalkyl, C₁₋₆-alkyl, C₂₋₄-acyl, R⁷ is hydrogen, C₃-6-cycloalkyl,C₁₋₆-alkyl, C₂₋₄-acyl, or R⁶ and R⁷ together with the nitrogen atom forma 5- or 6-membered saturated or unsaturated ring which may contain up totwo further heteroatoms from the group comprising oxygen, sulphur ornitrogen, whilst each additional nitrogen atom may be substituted byC₁₋₄-alkyl, preferably methyl; or R⁶ and R⁷ together with the nitrogenatom form phthalimido; R³ denotes hydrogen, halogen, C₁₋₆-alkyl,C₁₋₆-alkoxy, —CF₃ or —OCF₃; R⁴ denotes hydrogen, C₁₋₆-alkyl or halogen;R⁵ denotes hydrogen, C₁₋₆-alkyl, C₁₋₆-alkoxy, halogen, —CF₃ or —OCF₃,and the pharmacologically acceptable acid addition salts thereof, withthe exception of 2-(3-diethylamino-2-methyl)-imidazolidine. 13.Phenyliminoimidazolidines according to claim 12, wherein R¹ denoteshydrogen, C₁₋₄-alkyl, cyclopropyl, C₁₋₄-alkoxy, halogen, —CF₃ or —OCF₃;R² denotes —NR₆R₇ wherein R⁶ is hydrogen, C₃₋₆-cycloalkyl, C₁₋₄-alkyl oracetyl, R⁷ is hydrogen, cyclopropyl C₁₋₄-alkyl or acetyl, or R⁶ and R⁷together with the nitrogen atom form phthalimido; R³ is hydrogen,halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, —CF₃ or —OCF₃; R⁴ is hydrogen,C₁₋₄-alkyl, methyl, halogen; R⁵ is hydrogen, C₁₋₄-alkyl, C₁₋₄-alkoxy,halogen, —CF₃ or —OCF₃.
 14. Phenyliminoimidazolidines according to claim12, wherein R¹ is hydrogen, C₁₋₃-alkyl, n-butyl, isobutyl, sec.-butyl,preferably methyl, cyclopropyl, C₁₋₃-alkoxy, preferably methoxy,halogen, preferably chlorine or bromine, —CF₃; R² denotes —NR₆R₇ whereinR⁶ is hydrogen, cyclopropyl, C₁₋₄-alkyl, preferably methyl, R⁷ denoteshydrogen, C₁₋₄-alkyl, preferably methyl, or R⁶ and R⁷ together with thenitrogen atom form phthalimido; R³ denotes hydrogen, C₁₋₃-alkyl,n-butyl, isobutyl, sec.-butyl, preferably methyl, cyclopropyl,C₁₋₃-alkoxy, preferably methoxy, halogen, preferably chlorine orbromine, —CF₃; R⁴ denotes hydrogen, C₁₋₃-alkyl, n-butyl, isobutyl,sec.-butyl, preferably methyl, cyclopropyl, C₁₋₃-alkoxy, preferablymethoxy, halogen, preferably chlorine or bromine; R⁵ denotes hydrogen,C₁₋₃-alkyl, n-butyl, isobutyl, sec.-butyl, preferably methyl,cyclopropyl, C₁₋₃-alkoxy, preferably methoxy, halogen, preferablychlorine or bromine, —CF₃.
 15. Phenyliminoimidazolines according toclaim 12, wherein R¹ is hydrogen or methyl, R² is —NR⁶R⁷ wherein R⁶ andR⁷ independently of each other denote hydrogen, methyl or methoxy or R⁶and R⁷ together with the nitrogen atom form phthalimido; R³ denoteshydrogen, methyl, fluorine, chlorine or bromine; R⁴ denotes hydrogen, R⁵denotes hydrogen, methyl, chlorine or bromine.
 16. Aphenyliminoimidazolidine according to claim 12, which is2-(3-dimethylamino-2-methylphenylimino) imidazolidine,2-(6-bromo-3-dimethylamino-2-methylphenylimino)imidazolidine,2-(5-amino-2-chloro-4-methylphenylimino)-imidazolidine or2-(3-amino-2-methylphenylimino)-imidazolidine.
 17. Pharmaceuticalpreparation comprising a compound of general formula II according to oneof claims 12 to 16 as well as conventional diluents, excipients and/orcarriers.
 18. Process for preparing pharmaceutical preparationsaccording to claim 17, characterised in that compounds of generalformula II are mixed with conventional galenic diluents, excipientsand/or carriers.
 19. Use of compounds of general formula II as definedin any one of claims 12 to 16 for preparing pharmaceutical compositionsfor the treatment of urinary incontinence, particularly stressincontinence.
 20. Analogy processes for preparing compounds of generalformula

according to any one of claims 12 to 16 characterised in that an anilineof general formula

wherein R¹ to R⁵ are as hereinbefore defined is reacted with one of thefollowing compounds

2) CH₃OH 5 h refluxing or 1N NaOH in ethanol 1 h 60° C. and thecompounds obtained according to one of processes a-c are optionallyconverted into the pharmacologically acceptable acid addition saltsthereof.